Acute Effects of a Fungal Volatile Compound

Objective: 3-Methylfuran (3-MF) is a common fungal volatile product with active biologic properties, and previous studies have indicated a contribution to airway disease. The aim of the present study was to assess the acute health effects of this compound in humans. Design: Acute effects were assessed via chamber exposure to (1 mg/m(3)) 3-MF. Participants and measurements: Twenty-nine volunteers provided symptom reports, ocular electromyograms, measurement of eye tear film break-up time, vital staining of the eye, nasal lavage, acoustic rhinometry, transfer tests, and dynamic spirometry. Results: No subjective ratings were significantly increased during exposure. Blinking frequency and the lavage biomarkers myeloperoxidase and lysozyme were significantly increased, and forced vital capacity was significantly decreased during exposure to 3-MF compared with air control. Conclusions and relevance to clinical practice: Acute effects in the eyes, nose, and airways were detected and might be the result of the biologically active properties of 3-MF. Thus, 3-MF may contribute to building-related illness

Uptake, disposition and acute effects of inhaled organic solvents : Sex differences and influence of cytochrome P450 2E1 in human volunteers

The main aim of the present thesis was to study the influence of sex, cytochrome P450 2E1 and chlorzoxazone on the uptake and metabolism of solvents in humans. Sex differences in acute effects of organic solvents were also assessed. Study I: Many solvents, including acetone and toluene, are to a large extent metabolised by cytochrome P450 2E1 (CYP2E1). Also some pharmaceuticals such as chlorzoxazone are mainly metabolised by CYP2E1. Volunteers were exposed in an exposure chamber to acetone or toluene vapour at a dose equal to the Swedish occupational exposure limit, with and without intake of chlorzoxazone. The solvents were measured in inhaled air, exhaled air, capillary blood and urine. The levels of chlorzoxazone, its metabolite 6‑hydroxychlorzoxazone and hippuric acid, a metabolite of toluene, were also measured. Chlorzoxazone intake did not result in significant effects on acetone or toluene disposition; however, we found indications of slightly decreased biotransformation of acetone and possibly also of toluene after intake of chlorzoxazone. In addition, both acetone and toluene seem to delay the metabolism of chlorzoxazone. The most likely explanation for the effect is competitive inhibition of CYP2E1. Study II: To study the reliability of chlorzoxazone as an in vivo probe for CYP2E1 activity in humans, a series of experiments were performed. The influence of genotype, sampling time, dose, and ethanol intake were studied. In addition estimates of the intra- and inter-individual and short-term and long-term intra-individual variability in metabolic ratio were made. A positive correlation with body weight suggested dose-dependent metabolism of chlorzoxazone. The intra-individual metabolic ratio in long-term (yearly intervals) and short-term (weekly intervals) variability were similar. The metabolic ratio decreased with increasing chlorzoxazone dose, which supported that metabolism was dose-dependent. CYP2E1 genotypes or ethanol intake the preceding evening did not influence the metabolic ratio. In summary, the metabolism of chlorzoxazone is relatively stable over time, but appears to be dose-dependent at commonly used doses. It is therefore advisable to adjust the dose for body weight. Study III-V: To study possible sex differences in acute effects and the influence of sex on uptake and metabolism of solvents, women and men were exposed to vapours of m‑xylene, of 2‑propanol and to clean air in an exposure chamber. The volunteers were exposed for two hours at the Swedish occupational exposure limit. Effect measurements included blinking frequency, pulmonary function, nasal swelling, colour vision and inflammatory markers in nasal lavage. In addition, the subjects rated symptoms in a questionnaire. Body fat, weight and height were measured to assess the body build. The solvents and their metabolites were analysed in inhaled air, exhaled air, capillary blood, saliva and urine. The metabolic biotransformation capacity was assessed by phenotyping for CYP2E1 with chlorzoxazone and by genotyping for several metabolic enzymes. The women tended to rate symptoms higher than men. However, there were no significant sex related differences regarding symptom ratings in response to the solvent exposure. Women showed a small but significant decrease in some pulmonary function parameters after exposure to m‑xylene. The respiratory uptake was higher and the volume of distribution larger in males. The women had a slightly shorter half time of 2-propanol in blood but approximately four times higher 2-propanol levels in exhaled air at 10 min post-exposure and onwards. The most marked sex difference was that of salivary acetone, where levels increased more than 100-fold in women, but only about 10-fold in men after exposure to 2-propanol compared to clean air

Chloroanisoles and Chlorophenols Explain Mold Odor but Their Impact on the Swedish Population Is Attributed to Dampness and Mold

We recently reported that mold odor may be explained by chloroanisoles (CAs) formed by microbial biotransformation of chlorophenols (CPs) in legacy wood preservatives. Here we examine psychophysical aspects of CAs and trace their historic origins in buildings. Our exposure of healthy volunteers shows that 2,4,6-triCA is often perceived as unpleasant, characterized as musty or moldy and is detected at 13 ng/m3 or lower. Similar concentrations are reported in buildings with odor complaints. Scrutiny of written records reveal that new building construction methods were introduced in the 1950s, namely crawlspaces and concrete slabs on the ground. These constructions were prone to dampness and attack from wood decay fungi, prompting chemical companies and authorities to advocate preservatives against rot. Simultaneously, CPs became household chemicals used for example in indoor paints. When large-scale odor problems evolved, the authorities that once approved the preservatives attributed the odor to hidden mold, with no evidence that substantial microbial biomass was necessary for odor formation. Thereby the public remained unaware of problematic exposure to CPs and CAs. We conclude that the introduction of inappropriate designs of house foundations and CP-based preservatives once ignited and still provide impetus for indoor air research on “dampness and mold”

Establishment of Repeated In Vitro Exposure System for Evaluating Pulmonary Toxicity of Representative Criteria Air Pollutants Using Advanced Bronchial Mucosa Models

There is mounting evidence that shows the association between chronic exposure to air pollutants (particulate matter and gaseous) and onset of various respiratory impairments. However, the corresponding toxicological mechanisms of mixed exposure are poorly understood. Therefore, in this study, we aimed to establish a repeated exposure setting for evaluating the pulmonary toxicological effects of diesel exhaust particles (DEP), nitrogen dioxide (NO2), and sulfur dioxide (SO2) as representative criterial air pollutants. Single, combined (DEP with NO2 and SO2), and repeated exposures were performed using physiologically relevant human bronchial mucosa models developed at the air–liquid interface (bro-ALI). The bro-ALI models were generated using human primary bronchial epithelial cells (3–4 donors; 2 replicates per donor). The exposure regime included the following: 1. DEP (12.5 µg/cm2; 3 min/day, 3 days); 2. low gaseous (NO2: 0.1 ppm + SO2: 0.2 ppm); (30 min/day, 3 days); 3. high gaseous (NO2: 0.2 ppm + SO2: 0.4 ppm) (30 min/day, 3 days); and 4. single combined (DEP + low gaseous for 1 day). The markers for pro-inflammatory (IL8, IL6, NFKB, TNF), oxidative stress (HMOX1, GSTA1, SOD3,) and tissue injury/repair (MMP9, TIMP1) responses were assessed at transcriptional and/ or secreted protein levels following exposure. The corresponding sham-exposed samples under identical conditions served as the control. A non-parametric statistical analysis was performed and p < 0.05 was considered as significant. Repeated exposure to DEP and single combined (DEP + low gaseous) exposure showed significant alteration in the pro-inflammatory, oxidative stress and tissue injury responses compared to repeated exposures to gaseous air pollutants. The study demonstrates that it is feasible to predict the long-term effects of air pollutants using the above explained exposure system

Analysis of Acrolein Exposure Induced Pulmonary Response in Seven Inbred Mouse Strains and Human Primary Bronchial Epithelial Cells Cultured at Air-Liquid Interface

Background. Acrolein is a major component of environmental pollutants, cigarette smoke, and is also formed by heating cooking oil. We evaluated the interstrain variability of response to subchronic inhalation exposure to acrolein among inbred mouse strains for inflammation, oxidative stress, and tissue injury responses. Furthermore, we studied the response to acrolein vapor in the lung mucosa model using human primary bronchial epithelial cells (PBEC) cultured at an air-liquid interface (ALI) to evaluate the findings of mouse studies. Methods. Female 129S1/SvlmJ, A/J, BALB/cByJ, C3H/HeJ, C57BL/6J, DBA/2J, and FVB/NJ mice were exposed to 1 part per million (ppm) acrolein or filtered air for 11 weeks. Total cell counts and protein concentrations were measured in bronchoalveolar lavage (BAL) fluid to assess airway inflammation and membrane integrity. PBEC-ALI models were exposed to acrolein vapor (0.1 and 0.2 ppm) for 30 minutes. Gene expression of proinflammatory, oxidative stress, and tissue injury-repair markers was assessed (cut off: ≥2 folds; p<0.05) in the lung models. Results. Total BAL cell numbers and protein concentrations remained unchanged following acrolein exposure in all mouse strains. BALB/cByJ, C57BL/6J, and 129S1/SvlmJ strains were the most affected with an increased expression of proinflammatory, oxidative stress, and/or tissue injury markers. DBA/2J, C3H/HeJ, A/J, and FVB/NJ were affected to a lesser extent. Both matrix metalloproteinase 9 (Mmp9) and tissue inhibitor of metalloproteinase 1 (Timp1) were upregulated in the strains DBA/2J, C3H/HeJ, and FVB/NJ indicating altered protease/antiprotease balance. Upregulation of lung interleukin- (IL-) 17b transcript in the susceptible strains led us to investigate the IL-17 pathway genes in the PBEC-ALI model. Acrolein exposure resulted in an increased expression of IL-17A, C, and D; IL-1B; IL-22; and RAR-related orphan receptor A in the PBEC-ALI model. Conclusion. The interstrain differences in response to subchronic acrolein exposure in mouse suggest a genetic predisposition. Altered expression of IL-17 pathway genes following acrolein exposure in the PBEC-ALI models indicates that it has a central role in chemical irritant toxicity. The findings also indicate that genetically determined differences in IL-17 signaling pathway genes in the different mouse strains may explain their susceptibility to different chemical irritants

Measured odor thresholds of acrolein, crotonaldehyde, and hexanal.

<p>Each dot represents the threshold for one individual. The horizontal lines represent median.</p

Measures of odor and lateralization thresholds of acrolein, crotonaldehyde, and hexanal using a novel vapor delivery technique

<div><p>Introduction</p><p>Humans are exposed to aldehydes in a variety of environmental situations. Aldehydes generally have a strong odor and are highly irritating to the mucous membranes. Knowledge about odor perception and especially irritation potency in humans is thus essential in risk assessment and regulation, e.g. setting occupational exposure limits. However, data on odor and irritation are lacking or limited for several aldehydes. The aim of the study was to determine the odor and lateralization thresholds of some commonly occurring aldehydes. Acrolein and crotonaldehyde where chosen as they are formed when organic material is heated or burned, e.g. during cigarette smoking. n-Hexanal was also included as it is emitted from wood pellets and fibreboard.</p><p>Material and methods</p><p>To study odor and lateralization thresholds of these aldehydes, a novel, inexpensive olfactometer was designed to enable delivery of reliable and stable test concentrations and thus valid measures of thresholds. The delivery system consists of seven syringe pumps, each connected to a Tedlar bag containing a predefined concentration of the tested aldehyde vapor. To validate the threshold measures, a test-retest was performed with a separate method, namely odor delivery via amber bottles. Twenty healthy naïve individuals were tested.</p><p>Results</p><p>The median odor thresholds of acrolein, crotonaldehyde and hexanal were 17, 0.8, and 97 ppb, respectively. No lateralization threshold could be identified for acrolein (highest tested concentration was 2 940 ppb in 5 subjects), whereas the medians were 3 and 390 ppb for the latter two. In addition, odor thresholds for n-hexanal were also determined using two methods where similar results were obtained, suggesting that the olfactometer presentation method is valid.</p><p>Conclusion</p><p>We found olfactory detection and lateralization thresholds (except for acrolein) in alliance with, or lower than, previously reported in naïve subjects. The new olfactometer allows better control of presentations timing and vapor concentration.</p></div